Plague has devastated human and animal populations throughout history. In recent years, it has caused severe epidemics in many parts of the world, resulting in human deaths and severe economic losses. In addition, Yersinia pestis, the cause of plague, could be a devastating bioweapon. An intentional release of 50 kg of Y. pestis over a city of 5 million people could result in as many as 150,000 clinical cases and 36,000 deaths. Currently, no human vaccines are available for plague. A novel vaccine is needed that can protect against aerosolized exposure to Y. pestis. Viral vectors are among the many approaches currently being pursued to develop novel plague vaccines. Modified vaccinia Ankara (MVA) virus offers distinct advantages as a viral vaccine vector for the next generation of biodefense vaccines. Its safety and induction of mucosal immune responses has been well-documented for a variety of pathogens and MVA is being used as a second generation smallpox vaccine. In a related poxvirus vaccine vector, we demonstrated that several molecular elements significantly enhance the expression levels of Y. pestis F1 capsular antigen and augment the immune response. Our long-term goal is to optimize antigen expression by recombinant MVA and develop a highly safe mucosal MVA-based plague vaccine that protects against aerosol exposure to both Y. pestis and smallpox virus. The specific aims are as follows. 1) Construct and evaluate optimized MVA recombinant viruses that will express several Y. pestis antigens. 2) Test the efficacy of the recombinant MVA viruses for protection from aerosolized Y. pestis. 3) Evaluate vaccine protection against Y. pestfs antigen variants. 4) Evaluate the safety of the recombinant MVA/Y. pestis vaccines in immunodeficient mice. The combination of recombinant MVA vaccines that safely provides the most complete protection of mice from aerosol exposure to Y. pestis will be chosen for further analysis. In phase II, a multivalent MVA vaccine expressing the required antigens will be constructed and tested in mice and in non-human primates for protection against aerosolized Y. pestis and protection in experimental models of smallpox virus exposure. [unreadable] [unreadable]